1. Field of the Invention
This invention relates to analogues of the cyclic peptide hormone somatostatin and to methods of stimulating phagocytosis and of protecting tissues from toxins.
2. Description of the Prior Art
Somatostatin is a peptide hormone originally investigated because of its inhibitory effects against pituitary growth hormone, which is also known as somatotropin. Somatostatin is therefore sometimes known as somatotropin release inhibiting factor (SRIF). Recent studies have shown that pretreatment with exogenous somatostatin prevents cysteamine-induced duodenal ulcer, with minimal inhibition of gastric acid output (Schwedes et al, Eur. J. Pharm., 44, 195 (1977)). In addition, somatostatin has been shown to have a beneficial effect on experimentally induced pancreatitis (Schwedes et al, Horm. Metab. Res., 11, 142 (1979)) and adrenal and lung lesions (Schwedes et al, Metabolism Suppl., 1, 27, 1377 (1978)). Thus, somatostatin has been demonstrated to be useful in the protection of various tissues against damage, as well as for its original/property as a pituitary growth hormone inhibitor.
Additionally, various derivatives and analogues of somatostatin have been prepared for a variety of other purposes. The following U.S. patents are exemplary of these disclosures.
U.S. Pat. No. 4,310,518 discloses compounds of the formula ##STR1## wherein
Y is (CH.sub.2).sub.m wherein m is 0, 1 or 2 or sulfur such that the sulfur may be in any position along the chain;
R.sub.1 and R.sub.2 are independently lower alkyl, benzyl, substituted benzyl where the substituent may be one or two of lower alkyl, halogen, hydroxy, amino, nitro or lower alkoxy; and lower alkyl substituted with a 5- or 6-membered heterocyclic ring;
R.sub.3 is 3-indolylmethyl or substituted 3-indolylmethyl wherein the substituent may be lower alkyl, lower alkoxy, or halogen;
R.sub.4 is lower alkyl, hydroxy lower alkyl, benzyl, carboxy lower alkyl, amino lower alkyl or substituted benzyl wherein the substituent may be lower alkyl; lower alkoxy, hydroxy, halogen, amino or nitro, and
R.sub.5 is hydrogen, lower alkyl, benzyl, or substituted benzyl wherein the substituent is lower alkyl, lower alkoxy, hydroxy, halogen amino or nitro. These compounds are disclosed as having a more selective biological activity than somatostatin and to useful as growth hormone inhibitors and in the treatment of acromegaly, diabetes, diabetic retinopathy and peptic ulcers.
U.S. Pat. No. 4,360,516 discloses compounds of the formula ##STR2## wherein
Y is (CH.sub.2).sub.m wherein m is 0, 1, or 2 or sulfur such that the sulfur may be in any positiion along the chain;
R.sub.1 and R.sub.2 are independently lower alkyl, benzyl, substituted benzyl where the substituent may be one or two of lower alkyl, halogen, hydroxy, amino, nitro or lower alkoxy; and lower alkyl substituted with a 5- or 6-membered heterocyclic ring;
R.sub.3 is 3-indolylmethyl or substituted 3-indolylmethyl wherein the substituent may be lower alkyl, lower alkoxy, or halogen;
R.sub.4 is lower alkyl, hydroxy lower alkyl, benzyl, carboxy lower alkyl, amino lower alkyl or substituted benzyl wherein the substituent may be lower alkyl; lower alkoxy, hydroxy, halogen, amino or nitro, and
R.sub.5 is hydrogen, lower alkyl, benzyl, or substituted benzyl wherein the substituent is lower alkyl, lower alkoxy, hydroxy, halogen amino or nitro; and the two asymmetric centers marked with an asterisk (*) may be either D or L, provided the two centers of asymmetry are the same, while the other asymmetric centers are D. These compounds inhibit the release of glucagon, growth hormone and insulin, and certain of the compounds are also capable of inhibiting the release of gastric acid secretions. The compounds are said to be particularly useful in the treatment of acromegaly, diabetes, diabetic retinopathy and peptic ulcers.
U.S. Pat. No. 4,224,199 discloses compounds of the formula ##STR3## in which A represents an L-, D- or DL-5- or 6-fluoro-, bromo-, chloro-, or iodotryptophyl radical. These tetradecapeptides inhibit the release of growth hormone.
U.S. Pat. No. 4,316,890 discloses compounds of the formula ##STR4## in which
Bmp represents a desaminocysteine radical,
X represents Asn or His,
trp represents D-Trp that may be substituted in the phenyl ring by a halogen atom, and
Y represents the radical of a secondary .alpha.-amino acid having a maximum of 8 carbon atoms. These compounds have strong insulin-antagonistic and glucagon-antogonistic effects and are useful as antidiabetics.
U.S. Pat. No. 4,369,179 discloses compounds of the formula ##STR5## in which
A' represents H-Ala-Gly-, Ac-Ala-Gly-, H- or Ac-.
B represents Lys, Lys(Ac) or Lys(X) (wherein X is an .epsilon.-amino-protecting group)
trp represents L-Trp, D-Trp or an analogous radical which carries in the indole nucleus a halogen atom,
cys represents L-Cys or D-Cys and
Ac represents an acyl radical of an optionally substituted alkanecarboxyclic acid present at the free amino group. These compounds can be used as antidiabetics or to combat gastrointestinal bleeding.
U.S. Pat. No. 4,328,214 discloses compounds of the formula ##STR6## in which
trp represents L-Trp or D-Trp in which the phenyl ring may be substituted with a halogen atom, and
Gaba(Ar) represents the residue of a .gamma.-aminobutyric acid substituted with a cyclic hydrocarbyl radical. These compounds are disclosed to be antidiabetics.
U.S. Pat. No. 4,316,891 discloses compounds of the formula ##STR7## in which R.sub.1 is Ser or des R.sub.1, R.sub.2 is Ala or des R.sub.2. and R.sub.3 is Asn or des R.sub.3 and linear versions thereof in which the disulfide bridge is replaced by hydrogen sulfides. These compounds are more potent than somatostatin in inhibiting the release of growth hormone.
U.S. Pat. No. 4,280,953 discloses compounds of the formula ##STR8## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are hydrogen or a carbohydrate moiety selected from the group consisting of hexoses and amino-hexoses modified in the 2-position with an amide group, which hexose has the pyranose structure provided that at least one R group is not hydrogen, and pharmaceutically acceptable nontoxic salts thereof. These compounds have an extended lifetime compared to somatostatin and act as inhibitors of pituitary growth hormone secretion, glucagon and insulin secretion of the pancreas, and secretion of vasoactive intestinal polypeptides, secretion, gastrin, and gastric acid.
Additionally, various scientific journal publications have disclosed additional somatostation analogues. For example, Veber et al., Nature 292, 55-58 (1981), discloses compounds of the formula ##STR9## in which Aha is 7-aminoheptanoic acid and various fragments derived from this bicyclic structure. The bicyclic compounds were active in inhibiting growth hormone, glucagon, and insulin secretion.
However these compounds have been disclosed to be useful only for the specific purposes indicated, and there continues to be a need for active somatostatin analogues which protect blood vessel walls from lesions and activate phagocytes, two different uses of somatostatin.